Imaging of adult leukodystrophies

Imagem nas leucodistrofias do adulto

Claudia Costa Leite
1,2
, Leandro Tavares Lucato
3
, Germana Titoneli Santos
3
, Fernando Kok
4
, Anderson
Rodrigues Brando
4
, Mauricio Castillo
2
ABSTRACT
Leukodystrophies are genetically determined white matter disorders. Even though leukodystrophies essentially affect children in early
infancy and childhood, these disorders may affect adults. In adults, leukodystrophies may present a distinct clinical and imaging
presentation other than those found in childhood. Clinical awareness of late-onset leukodystrophies should be increased as new therapies
emerge. MRI is a useful tool to evaluate white matter disorders and some characteristics findings can help the diagnosis of
leukodystrophies. This review article briefly describes the imaging characteristics of the most common adult leukodystrophies.
Keywords: leukodystrophies, adult form, magnetic resonance imaging, imaging.
RESUMO
Leucodistrofias so doenas geneticamente determinadas. Apesar das leucodistrofias afetarem principalmente crianas lactentes e
infantes, estas doenas podem acometer a faixa etria adulta. Nos adultos, as leucodistrofias podem ter uma apresentao clnica e de
imagem distinta daquela da infncia. Um aumento na suspeita clnica de leucodistrofias com incio tardio deve ocorrer associado ao
aparecimento de novas alternativas teraputicas. Este artigo de reviso descreve sumariamente as caractersticas de imagem nas
leucodistrofias no adulto.
Palavras-chave: leucodistrofias, formas do adulto, ressonncia magntica, mtodos de imagem.
Leukodystrophies are genetically determined disorders
that primarily affect the white matter. In recent years,
advances in molecular genetics have made the characteriza-
tion and diagnosis of many leukodystrophies possible with
the identification of defective genes. Furthermore, the wide-
spread use of magnetic resonance imaging (MRI) allows the
identification of white matter changes even at the beginning
of the disease, in pre-symptomatic patients and carriers.
Even though leukodystrophies essentially affect children and
present in early infancy and childhood, these disorders may
affect adults and many times, with a distinct clinical and
imaging presentations other than those found in childhood.
As leukodystrophies are a heterogeneous group of diseases,
many pathological findings are common to all, such as demye-
lination, hypomyelination and vacuolization. Commonly the
white matter involvement is bilateral and symmetric.
Adult leukodystrophies or late-onset leukodystrophies
can manifest initially as isolated psychiatric symptoms such
as cognitive decline, behavioral problems, memory loss,
psychosis and dementia. Other clinical manifestations
include motor signs, peripheral neuropathy, bulbar dysfunc-
tion and epilepsy. Furthermore, in adults, disease progres-
sion is slower in comparison to the childhood subtypes of
the same leukodystrophy.
Clinical awareness of late-onset leukodystrophies should
be increased, as new therapeutic approaches have been
developed, such as stem cell transplantation, enzyme
replacement and gene therapy
1
. MRI is a useful tool to evalu-
ate new forms of leukodystrophies and to allow longitudinal
studies of disease progression
2,3,4
. The aim of this review is to
briefly describe the imaging characteristics of the most com-
mon adult leukodystrophies.
IMAGING FINDINGS
X-linked adrenoleukodystrophy (X-ALD)
X-linked adrenoleukodystrophy (X-ALD) is associated
with the accumulation of very long chain fatty acids
(VLCFA) in serum, neural tissues and adrenal glands. The
1
Departamento de Radiologia, Faculdade de Medicina, Universidade de So Paulo, Sao Paulo SP, Brazil;
2
Radiology Department, School of Medicine, University of North Carolina, Chapel Hill North Carolina, United States;
3
Instituto de Radiologia, Hospital das Clnicas, Faculdade de Medicina, Universidade de So Paulo, Sao Paulo SP, Brazil;
4
Departamento de Neurologia, Faculdade de Medicina, Universidade de So Paulo, Sao Paulo SP, Brazil.
Correspondence: Claudia Costa Leite; Radiologia, Faculdade de Medicina USP; Av. Dr. Ovidio Pires Campos, s/n Inrad Portaria 5, Ressonncia Magntica;
05403-010 So Paulo SP, Brasil.
Conflict of interest: There is no conflict of interest to declare.
Received 23 April 2014; Received in final form 07 May 2014; Accepted 27 May 2014.
DOI: 10.1590/0004-282X20140095
VIEW AND REVIEW
625
mutation associated to ALD-X is in the ABCD1 gene. The
cell accumulation of VLCFA causes demyelination in the
central nervous system (CNS) and cell destruction in
the adrenal glands. As an X-linked inherited disease,
X-ALD affects mostly males. In adult males the predominant
form is adrenomyeloneuropathy. ALD mutation may occur
in women and they sometimes manifest milder symptoms
5
.
Adrenomyeloneuropathy is a slowy progressive disease
that presents with adrenal insufficiency, distal axonopathy
(predominantly affecting the corticospinal tracts and dorsal
columns of spinal cord) and peripheral neuropathy
1,3
. The
clinical presentation is usually spastic paraparesis. Brain
MRI shows signs of involvement of the corticospinal tracts,
dorsal columns, corpus callosum and periventricular white
matter (Figure 1). Around 20% of adrenomyeloneuropathy
patients develop a more severe phenotype called adult
cerebral adrenoleukodystrophy. Psychiatric signs, followed
by motor signs, optic atrophy, epilepsy and death character-
ize this form of cerebral ALD.
As in childhood ALD, contrast enhancement can be
seen in the periphery of the white matter lesions
3
(Figure 2). Cerebral adult form can manifest as asymmetric
focal lesions sometimes mimicking a tumor, and in
some reports has been related to previous traumatic epi-
sodes (Figure 3)
5,6
.
Heterozygous women are usually asymptomatic or pre-
sent brisk tendon reflexes and impaired vibration sensation.
An ill-defined pain syndrome may occur. In 15% of females
progressive spastic paraparesis can ensue around 40 years
of age. Very rarely, the X-ALD women present adrenal insuf-
ficiency or brain involvement. Brain MRI can be normal or
be similar to that seen in adrenomyeloneuropathy
3,5,7
.
Metachromatic leukodystrophy
Metachromatic leukodystrophy is an autosomal recessive
lysosomal disease caused by a deficiency of the enzyme aryl-
sulfatase A (ARSA) that leads to the accumulation of sulfatides
in oligodendrocytes, Schwann cells and some neurons causing
Figure 1. Adrenomyeloneuropathy with brain involvement in a 36-year-old male. Axial FLAIR (A and B) demonstrates bilateral
hyperintensities in the deep white matter, body of the corpus callosum and internal capsules. Axial enhanced T1-weighted images
(C and D) shows enhancement of the internal capsules and the body of the corpus callosum (arrows).
Figure 2. Adult cerebral leukodystrophy in a 54-year-old male with fast cognitive decline and pyramidal symptoms. Axial FLAIR and
T2 (A and B) demonstrates bilateral periventricular, subcortical frontal and parieto-occipital white matter involvement. Note
also hyperintensity in the internal capsules. Contrast enhanced axial T1-weighted images (C) shows faint enhancement in the
periphery of the frontal lesions (arrows).
626 Arq Neuropsiquiatr 2014;72(8):625-632
demyelination both in the central as well as in the peripheral
nervous systems
3
. More than 100 mutations causing meta-
chromatic leukodystrophy have been identified.
The adult-onset form, which occurs after 16 years of age,
accounts for 20% of cases. The disease can manifest as late
as the seventh decade of life
2
. In adulthood the main clinical
presentations are psychiatric problems (cognitive, behavioral
problems and memory deficits) sometimes mimicking
schizophrenia followed by motor signs, such as spastic para-
paresis, cerebellar ataxia and mild polyneuropathy. The dis-
ease course is self-limiting
3,8
.
MRI shows a bilateral periventricular leukoencephalopa-
thy predominantly in the frontal regions, sparing the U-fibers
in the initial phase of the disease. The corpus callosum can
be affected. Cortical atrophy is also seen predominantly late
in the course of the disease
9,10,11
.
Krabbes disease (Globoid cell leukodystrophy)
Krabbes disease is an autosomal recessive lysossomal stor-
age disease caused by the deficiency of b-galactocerebrosidase
(GALC) enzyme activity. The GALC defect leads to the accu-
mulation of galactocerebroside and psychosine, which causes
oligodendrocyte apoptosis and gliosis. The gene encoding for
GALC is localized to chromosome 14q31. Unfortunately, nei-
ther the galactocerebrosidase activity nor the gene mutation
can define the genotype in Krabbe disease
12
.
Adult Krabbe patients are older than 16 years, and the
disease can manifest as late as in the fifth decade of life.
Clinically late onset forms present pyramidal tract involve-
ment with spastic paraparesis or tetraparesis. A peripheral
demyelinating polyneuropathy occurs in up to 60% of patients,
sometimes being asymmetric and involving bulbar muscles.
Progressive cognitive decline, seizures and cortical blindness
can also ensue. The disease progression is slow
1,3,13
.
On MRI, the deep supratentorial and cerebellar white
matter are affected. Pyramidal tracts, splenium of corpus
callosum and optic radiation can present hyperintensity on
T2-weighted and FLAIR images. The signal abnormalities
in the corticospinal tracts start in the perirolandic regions
and extend to corona radiata, internal capsules, cerebral
peduncles, ventral part of the pons and medulla bilaterally
(Figure 4). Corpus callosum atrophy can also be seen. In rare
occasions, MRI can be normal
3,13
.
Alexander disease
Alexander disease is a leukodystrophy characterized
pathologically by diffuse Rosenthal fibers accumulation in
astrocyte cytoplasm. The defect associated with this disease
is located in the gene encoding for GFAP (glial fibrillary
acid protein). After the identification of the gene defect,
the number of adult-onset cases described in the literature
has increased.
In Alexander disease, Rosenthal fibers are scattered
throughout the cortex and in white matter and are most
numerous in the subpial, perivascular and subependymal
regions. The adult-onset form is diagnosed after 12 years
of age up to the eighth decade of life. Clinical presentation
includes a slowly progressive bulbar dysfunction (dysphagia,
dysarthria, dysphonia), pyramidal signs and ataxia, with nor-
mal psychic and intellectual functions. When present, pal-
atal myoclonus is suggestive of this diagnosis
14,15,16
.
MRI shows mild- to- severe atrophy of the medulla oblon-
gata extending caudally to the cervical spinal cord, some-
times associated with signal abnormalities (Figure 5).
Midbrain tegmentum atrophy has also been described, with
preservation of the pontine base and this finding is quite
specific of adult-onset Alexander disease
17
. Basal ganglia
abnormalities (diffuse or patchy) have also been described,
especially in patients under 40 years of age. In a few cases, peri-
ventricular garland that is typical of the juvenile form has been
documented. Contrast enhancement is also reported in some
patients especially in those under 40 years of age
14
. Relatives
Figure 3. Adult cerebral leukodystrophy with an asymmetric presentation in a 28-year-old male who had a direct trauma to the right
parietal region a few months earlier. Axial FLAIR (A) demonstrates a subcortical lesion in the right parietal lobe. Enhanced axial
T1-weighted image (B) shows a peripheral discontinuous rim of enhancement. Coronal T2-weighted image (C) shows extension of the
signal abnormality to the internal capsule. Axial diffusion-weighted image (D) shows a hyperintense rim in the lesion.
Claudia Costa Leite et al. 627
with the gene mutation but without clinical manifestations
(asymptomatic Alexander disease) can present a periventricu-
lar band of signal abnormality on MRI
15
.
Vanishing white matter disease
Vanishing white matter disease patients have mutations
in the eIF2B (eukaryotic initiation factor 2B) complex genes.
A mild variant of this disease has been described in adoles-
cence and adulthood. The clinical onset in the juvenile or
adult forms is characterized by migraine, psychiatric symp-
toms and dementia. Pseudobulbar palsy and progressive
spastic paraparesis have also been described.
Women present ovarian insufficiency (dysgenesis) and
leukodystrophy, a condition known as ovarioleukodystrophy.
The ovarian failure may precede neurologic symptoms
7,18
.
MRI can show enlargement of the lateral ventricles and
the white matter can be normal or present hyperintensity
on T2-weighted and FLAIR images (Figure 6). Limited sub-
cortical white matter hypointensity on FLAIR associated to
the cystic breakdown or cavitation can be seen
19
.
Leukoencephalopathy with axonal spheroids and
pigmented glia
This very rare entity encompasses leukoencephalopathy
with spheroids (HDLS) and pigmentary leukodystrophy
(POLD), whether they represent the same disease or not is
still controversial. They are hereditary diseases that unlike
other leukodystrophies manifests exclusively in adults, most
cases occurring in the 20- to 50-year age range. The clinical
picture consists of behavioral changes, dementia, motor
impairment (Parkinsonism, paraparesis or tetraparesis and
ataxia) and epilepsy. There is an apparent autosomal
dominant inheritance for HDLS and an autosomal recessive
or dominant one for POLD
2,20
.
CT can show atrophy predominantly in the frontal lobes.
MRI in HDLS shows frontal lobe atrophy and white matter
lesions that can be diffuse, patchy or confluent and predomi-
nantly frontal or frontoparietal. The lesions are non-enhan-
cing and hyperintense on T2-weighted images. Signal
intensity abnormalities in the internal capsules and corti-
cospinal tracts have also been described
2,4,20
.
Figure 5. Adult-onset Alexander disease in a 47-year-old female. Axial FLAIR images shows atrophy of the medulla with hyperintensity
in the projection of corticospinal tracts (arrow in A), bilateral hyperintensity in the deep cerebellar white matter (B) and in the
cerebral hemispheres (C). Enhanced sagittal T1-weigted image (D) shows medulla and upper cervical cord atrophy (arrow).
Figure 4. Late-onset Krabbe disease. Axial T2-weighted images (A and B) disclose bilateral and symmetric hyperintensity involving
the corticospinal tracts from the centrum semiovale to the posterior limb of the internal capsule. There are similar changes
appreciated in the splenium of corpus callosum.
628 Arq Neuropsiquiatr 2014;72(8):625-632
Adult-onset autosomal dominant leukodystrophy
(ADLD)
Adult-onset autosomal dominant leukodystrophy (ADLD)
is a very rare slowly progressive neurological disorder
characterized by symmetric widespread myelin loss in the
CNS. Patients usually present in the fourth to sixth decades
of life with autonomic symptoms, bowel and bladder dysfunc-
tion, and orthostatic hypotension, later progressing to pyr-
amidal symptoms and ataxia
21
. The gene that causes ADLD
is located in chromosome 5q31. Two neuropathological obser-
vations make this leukodystrophy unique: preservation of oli-
godendroglia in the presence of subtotal demyelination and
a lack of astrogliosis
22
.
The signal intensity abnormalities are most prominent in
the frontoparietal white matter, cerebellar peduncles, corti-
cospinal tracts and corpus callosum (Figure 7). The periven-
tricular white matter is relatively spared. The changes in the
uppermost corticospinal tracts underlying the motor cortex
may represent the earliest radiologic imaging manifestation
of the disease and also can be seen in asymptomatic family
members. Extensive involvement of the cerebral white
matter may be seen in the final stages of the disease. The
MRI lesion pattern, in combination with the typical clinical
symptoms and mode of inheritance, enable the diagnosis
of ADLD
23
.
Cerebrotendinous xanthomatosis
Cerebrotendinous xanthomatosis is a rare autosomal
recessive disease of the lipid metabolism. It is characterized
by the deficiency of the mitochondrial enzyme sterol
27-hydroxylase (CYP27) that is involved in the synthesis of
bile acids from cholesterol leading to the accumulation of
cholesterol and cholestanol. Storage compounds can form
xanthomata in various tissues. Initial symptoms occur in
childhood with mental retardation, juvenile cataracts or
chronic diarrhea. Progressive neurological deterioration
occurs in adolescence or adulthood.
The clinical presentation includes psychiatric symptoms,
spastic paraparesis, cerebellar ataxia, polyneuropathy.
Tendon xanthomatas can be found, especially in the
Figure 6. Vanishing white matter in a 48-year-old male. Axial T2-weighted (A) and FLAIR (B) images showing diffuse bilateral
hyperintensity in the white matter extending to the U fibers, internal and external capsules, with cavitations in the deep white matter.
Figure 7. Adult-onset autosomal dominant leukodystrophy with autonomic symptoms (ADLD) in a 54-year-old man. Axial T2
images (A and B) shows high signal in the deep cerebellar white matter, middle cerebellar peduncles and pons. Axial FLAIR images
(C and D) demonstrate diffuse hyperintensities in the periventricular and subcortical white matter, splenium of corpus callosum
and atrophy. The corticospinal tracts show hyperintensity in the internal capsules (arrows in C) and pons (arrows in B).
Claudia Costa Leite et al. 629
Achilles tendon
3
. Early treatment is important as patients
can benefit from therapy
24
.
MRI shows hyperintensity on T2-weighted images in the
dentate nucleus, cerebellar white matter (Figure 8), cerebel-
lar peduncles, pyramidal tracts, periventricular white matter,
corpus callosum and basal ganglia. In the late stages, hypoin-
tensity on T2-weighted images can be seen in the dentate
nucleus
3
. Brain and cerebellar atrophy can also be seen
24
.
Nasu-Hakola disease
Nasu-Hakola disease (NHD) or polycystic lipomembra-
nous osteodysplasia with sclerosing leukoencephalopathy
is a rare, autosomal recessive disorder, caused by mutations
in two genes: TREM 2 and DAP 12. NHD is characterized by
a combination of diffuse bone cysts and pre-senile dementia.
Most of the NHD patients first present in early adulthood
with skeletal abnormalities (osseous phase). Neurological
symptoms manifest in the fourth decade of life as psychiatric
symptoms and memory loss (neuropsychiatric phase), which
precedes the dementia phase. Progressive decline evolves to
a profound dementia and death by the fifth decade of life
25
.
Bone imaging shows multiple cystic-like lesions leading
to fractures in the wrists and ankles. In the brain, calcifica-
tions in the basal ganglia can be seen on CT, while cortical
atrophy and nonspecific white matter involvement are best
appreciated using MRI (Figure 9)
26,27
.
Cadasil and carasil
CADASIL and CARASIL are small vessel diseases asso-
ciated to ischemia and/or hemorrhage, diffuse white matter
disease and vascular dementia
28
.
CADASIL is an acronym standing for cerebral autosomal
dominant arteriopathy with subcortical infarcts and
leukoencephalopathy; while CARASIL is similar, but is
recessive instead of dominant.
CADASIL is caused by the mutation in NOTCH3 gene
and affects adolescents and adults presenting with
migraines, transient ischemic attacks, strokes, psychiatric
Figure 8. Cerebrotendinous xanthomatosis in a 47-year-old male with ataxia. Coronal T2-weighted imaging (A) demonstrates
hyperintensity in the deep cerebellar white matter. Axial T2* (B) and FLAIR images (C and D) show hyperintensity in the cerebellar
hemispheres, cerebral peduncles (arrows in C), globus pallidus and deep cerebral white matter. Notice a hypointense area in B,
seen in the left cerebellar hemisphere, a finding that can be appreciated eventually in the disease.
Figure 9. Nasu-Hakola disease in a 46-year-old man. Unenhanced CT (A) shows punctuate calcifications in the lentiform nuclei.
Axial FLAIR image (B) demonstrates mild hyperintensity in the periventricular white matter. Note cortical atrophy. A radiograph
of the hands (C) demonstrates cystic lesions in the carpal bones bilaterally (arrows).
630 Arq Neuropsiquiatr 2014;72(8):625-632
disorders and cognitive decline. CADASIL is the most com-
mon cause of inherited vascular dementia in adults.
White matter involvement is usually found in the
external capsules and anterior temporal poles, this last loca-
tion being highly suggestive of CADASIL. The corpus callo-
sum is less frequently involved. MRI changes precede the
onset of symptoms by 10-15 years. On T2-weighted and
FLAIR images there are round, predominantly periventricu-
lar lesions in the centrum semiovale, external capsules and
anterior temporal poles (Figure 10). The signal changes tend
to be symmetrical. Basal ganglia, thalamus, brainstem and
corpus callosum can also be involved. Enlarged Virchow-
Robin spaces, small foci of restricted diffusion suggesting
recent infarcts and microhemorrhage on T2* images were
described as well. The MRI abnormalities appear in the
fourth decade of life and increase with age
28,29
.
CARASIL affects a younger population than CADASIL.
The neurological symptoms are transient ischemic attacks
and strokes. The MRI findings are diffuse white matter
changes and lacunar infarcts
30
.
Other small vessel, genetically inherited disease, is the so-
called autosomal dominant retinal vasculopathy with leuko-
dystrophy and TREX1 mutation. It can present with white
matter involvement in the brain and cerebellum and areas
of contrast enhancement.
Other reported instances of adult-onset leukodystrophies
include Pelizaeus-Merzbacher disease and vacuolating megalen-
cephalic leukoencephalopathy with subcortical cysts. Pelizaeus-
Merzbacher is rarely described in adults and the MRI findings
include white matter diffuse T2-hyperintensities sparing small
focal areas. MRI of patients with vacuolating leukoencephalopa-
thy with subcortical cysts in adults shows bilateral extensive
white matter changes with cysts in the temporal regions, some-
times the patients also present megalencephaly
31,32
.
Final remarks, leukodystrophies should be kept in mind in
the differential diagnosis of bilateral white matter disease in
adults. Some imaging findings can help suggest a final dia-
gnosis. Involvement of the corticospinal tract can be seen in
Krabbes disease, adrenomyeloneuropathy, cerebrotendinous
xanthomatosis and ADLD. Contrast enhancement can be seen
in the adult cerebral form of ALD and Alexander disease. In
adult-onset Alexander disease atrophy and signal abnormal-
ities can be seen in the medulla oblongata and cervical cord.
Limited subcortical hypointensity on FLAIR images is present
sometimes in ovarioleukodystrophy. Dentate nucleus and
cerebellar white matter abnormalities can occur in cerebroten-
dinous xanthomatosis. Brain calcifications, white matter
abnormalities and bone cysts are present in Nasu-Hakola dis-
ease. In CADASIL involvement of the external capsules and
anterior temporal poles are characteristic.
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